Manganese neurotoxicity: lessons learned from longitudinal studies in nonhuman primates

Exposure to excess levels of the essential trace element manganese produces cognitive, psychiatric, and motor abnormalities. The understanding of Mn neurotoxicology is heavily governed by pathologic and neurochemical observations derived from rodent studies that often employ acute Mn exposures. The comparatively sparse studies incorporating in vivo neuroimaging in nonhuman primates provide invaluable insights on the effects of Mn on brain chemistry.

The purpose of this review is to discuss important aspects of Mn neurotoxicology and to synthesize recent findings from one of the largest cohorts of nonhuman primates used to study the neurologic effects of chronic Mn exposure.

We reviewed our recent in vivo and ex vivo studies that have significantly advanced the understanding of Mn-induced neurotoxicity. In those studies, we administered weekly doses of 3.3-5.0 (n=4), 5.0-6.7 (n=5), or 8.3-10.0 mg Mn/kg (n=3) for 7-59 weeks to cynomolgus macaque monkeys. Animals expressed subtle deficits in cognition and motor function and decreases in the N-acetylaspartate-to-creatine ratio in the parietal cortex measured by magnetic resonance spectroscopy reflective of neuronal dysfunction. Impaired striatal dopamine release measured by positron emission tomography was observed in the absence of changes in markers of dopamine neuron degeneration. Neuropathology indicated decreased glutamine synthetase expression in the globus pallidus with otherwise normal markers of glutamatergic and GABAergic neurotransmission. Increased amyloid beta (A4) precursor-like protein 1 gene expression with multiple markers of neurodegeneration and glial cell activation was observed in the frontal cortex.

These findings provide new information on mechanisms by which Mn affects behavior, neurotransmitter function, and neuropathology in nonhuman primates.